NDA 21196

Xyrem® for Narcolepsy

Orphan Medical, Inc.

Comments About
Sleepwalking

Background

In this NDA and especially in the Scharf Study, the term
“sleepwalking” has been used as a verbatim (investigator) term for a common
adverse event. The COSTART preferred term under which this entity has beencoded is “sleep disorder.”

The sponsor has not discussed this adverse event, either in
the original NDA submission or in this Amendment. Given the frequency and potential/actual
consequences of this adverse event (see below) I have chosen to discuss it
further briefly

In most instances of “sleepwalking” in this NDA, a detailed
description of patient behavior during that adverse event is not available.

The medical term “sleepwalking” refers to a non-REM
parasomnia classified as an arousal disorder. During episodes patients exhibit
complex behaviors including automatic and semi-purposeful motor activities:
sitting up in bed, walking, climbing stairs, opening and closing windows and even
more complex tasks, such as preparing food, may be features. Acts that are
destructive or harmful may be seen, such as throwing objects, and climbing out
through a window. During and immediately following episodes patients are
confused; they have amnesia for the episodes. It is not at all clear that
the term “sleepwalking” has a similar connotation when used in this NDA, or
that it refers to a single clinical entity. In the majority of instances of
sleepwalking in the Scharf study, this term appears to be derived from daily
logs maintained by patients

There does not appear to be an association between
narcolepsy and typical sleepwalking as defined in the paragraph above. However
about 50% of narcoleptic patients have periods of automatic behavior that are described
as memory lapses or blackouts; patients have amnesia for their activities
during these episodes. Semi-purposeful activity ispossible during such episodes which may manifest with phenomena
such as walking into objects, getting lost while driving, and writing
unintelligibly. Such episodes are believed to be due to micro-sleeps that
intrude into wakefulness, and are most frequent in the mornings. Again there is
no information supplied with the NDA that would strongly suggest that any of
the “sleepwalking” episodes correspond to automatic behavior occurring as part
of narcolepsy.

Incidence Of “Sleepwalking” In Xyrem® NDA

Controlled Clinical Trial OMC-GHB-2

The incidence of adverse events coded under the COSTART
preferred term “sleep disorder” is as follows among the 4 treatment groups

Dose
Group

Total
Number Randomized

Number
of Patients with “Sleep Disorder”

(COSTART)

%of Patients with “Sleep Disorder”

(COSTART)

Placebo

34

1

2.9

3
g/day

34

2

5.9

6
g/day

33

4

12.1

9
g/day

35

5

14.3

The sponsor has attempted to characterize the term “sleep
disorder” further in the following table which I have copied from the OMC-GHB-2
clinical trial report

Integrated Clinical Trials (of which OMC-GHB-2 is a component)

“Sleep disorder”
(COSTART) occurred in 46/402 (11.4%) of patients participating in these trials.
There was no dose-response seen and the sponsor has not characterized this
adverse event further except in the case of those participating in OMC-GHB-2.
Thus it is unclear how many patients recorded as having a “sleep disorder”
(COSTART) might have been considered to have “sleepwalking”

Scharf Trial

Based on my review of all the Case Report Forms for this
study, 45/143 (31.5%) of patients were listed as having one or more episodes of
“sleepwalking.” A single patient (# 01-042, initials MJM) is described as
having 346 episodes, and many patients had multiple episodes.

The patients listed as having “sleepwalking” constitute the
entire cohort of those coded under the COSTART preferred term “sleep disorder”
in this study

Characterization Of “Sleepwalking” Episodes

As already indicated the sponsor has not provided more
detailed descriptions of patient behavior during these episodes except in a
very small number of instances.

I have not attempted to characterize the “sleepwalking”
episodes in regard to patient demographics, duration, severity and seriousness
of episodes, GHB dose at onset, concomitant medications and illnesses, outcome
and other parameters. I currently lack both the time and resources to perform
such an analysis. The sponsor should, however, be required to perform such an
analysis prior to approval. Such episodes, regardless of their etiology, have
had serious consequences as outlined below.

Consequences Of “Sleepwalking” In Xyrem® NDA

Narratives are provided below for patients who were reported
to have events of serious or potentially serious consequence during episodes of
“sleepwalking.” These consequences include taking an overdose of GHB as well as
other actions. Several of these narratives are elsewhere in this review but are
reproduced here for convenience. All instances occurred in the Scharf study.

This 46 year old woman with narcolepsy, who
sustained a skull fracture 5 years prior to study entry, took GHB in a variable
dose of 4.5 to 10.5 g/day in 2 or 3 divided doses despite being prescribed 7.5
g/day (this is not consistent with what has been entered in the medication logs
in the Case Report Form. About 4 months after entering the study she reported
symptoms of nausea, a tipsy feeling, blurred vision, and a swollen face and
hands. These symptoms persisted for 14 days, no action was taken, and her doses
subsequently were variable and as high as 10.5 g/day. She continued in the
study for a further 4 years when she was discontinued on account of
non-compliance which involved not submitting daily sleep log diaries and
modifying dosing schedules without prior consultation with Dr Scharf.

A number of unexplained fits of laughter (termed
“hysterical” in one instance, and “uncontrollable” at other times), and episodes of “sleepwalking” (during one of
which she tried to drink nail polish remover). Episodes of headache,
nausea, dizziness, blurred vision, enuresis, “fogginess”, “stumbling
around-unsure of self on feet after gamma”, “drugged effect, vision blurred,
unsteady on feet”, “drunken stupor; rage”, other similar events, and
sleeplessness, were also noted during the study.

A telephone contact with the patient 12 ½ years
after she discontinued from the study indicated that her neurological adverse
events, with the exception of blurred vision, had resolved once GHB was
discontinued.

This 63 year old man had a history of narcolepsy
and sleep apnea. as well as hypertension. Initial physical examination is
reported to have shown a “mild-to-moderate degree of oropharyngeal compromise.”

He began taking GHB in a dose of 4.5 g daily.About
11 months after enrolling, in an incident attributed to possible sleepwalking
he ingested an additional estimated 9 g of GHB in addition to his firstnightly 3 g dose of the drug. He drove
himself to an emergency room, where he was administered ipecac and slept for 2
hours

Approximately 1 ½ years after enrolling in the study he
was hospitalized after an overdose of GHB 18 g, again attributed to
sleepwalking. At the time of hospitalization he was comatose and unresponsive.
He needed intubation and artificial ventilation, and awoke 6 hours later. He
continued in the study.

Other significant items of information regarding this patient
are as follows

·He had many episodes of
sleep walking and multiple episodes of urinary incontinence.

·In 2 instances episodes of
sleep walking and urinary incontinence are listed in the Case Report Form as
occurring on the same day although there is no evidence presented that they
occurred at the same time.

·On the days when both
incontinence and sleep walking are listed as having occurred, the patient’s
prescribed dose was 7.5 g/day

·As noted above this had
multiple episodes of sleep walking that did not occur on the same days as his
episodes of incontinence.

·He
also reported muscle jerks over the front of his trunk over a period of several
years while taking GHB.These were
stated to be most prominent when lying in bed in the morning as the last dose
of GHB was wearing off; they could be controlled voluntarily and would
disappear with ambulation, returning when at rest.

·He
developed congestive heart failure during the study and died about 5 years
after study entry. While participating in the study he underwent a thoracotomy
for a right lung nodule that was confirmed to be a squamous cell carcinoma.

This 65 year old woman had a history of obesity,
sleep apnea on treatment, and narcolepsy. She began taking GHB in a dose of 4.5
g daily.

About
4 ½years after study entry she was
reported to have taken an overdose of GHB, consuming a third nightly dose
instead of merely two doses. The patient’s daughter reported that the patient
was shortly afterward incontinent of urine, awoke and (for unclear reasons) was
covered with spaghetti sauce. She also appeared dazed and confused. Her diaries
are unavailable for that period and it is therefore unclear what her regular
dose of GHB was at the time. She was taken to an emergency room but had
recovered by that time. She was reported to have continued GHB
after that episode but ceased returning any daily diaries at all beginning
about 5 ¼years after study entry and
was therefore recorded as having left the study on account of non-compliance.
Repeated letters to the patient from the study center were reportedly
unanswered. Further information about this patient is unavailable.

During
her participation in the study she was also recorded to have multiple episodes
of sleepwalking and multiple additional episodes of urinary incontinence, not
apparently occurring contemporaneously. She was also seen at an
emergency room for an episode of somnolence which was felt to be related to her
sleep apnea. She reported swollen ankles and wrists, and pain, numbness and
tingling in her feet.

(It is not clear from the above or from the Case
Report Form whether the overdose occurred during an episode that would have
been considered to represent “sleepwalking”)

Patient 01-206 (Initials DRS)

This 62 year old woman had a history of narcolepsy,
hypertension and heavy smoking. She began taking GHB in a dose of 3 g/day.

While participating in the trial she had 7 episodes of
sleep walking. 2 episodes which occurred, separated by a 2-day interval, 7 ½
months after she entered the study, led to her discontinuing GHB. During each
of these episodes she was found by her husband with a burning cigar or
cigarette in her hand, apparently not aware of having been smoking. On one of
these occasions she was found in a room other than their bedroom asleep with a
cigar in her hand. On the second occasion the cigarette was found to be burning
her nightgown; her husband threatened at that point to leave her unless she
stopped taking GHB. The patient’s entries in her daily sleep log indicate that
she was unaware of her actions during these episodes and had no personal
recollection of them subsequently .

Reviewer’s Comments

·In the absence of adequate clinical descriptions in
most instances it is unclear what the adverse event investigator term
“sleepwalking” represents, or whether it refers to single or multiple entities.

·Regardless of what the term “sleepwalking” means in the
context of this NDA, it is clear that such episodes are common; almost one-third
of patients participating in the long-term Scharf safety study did have one or
more such occurrences, and a single patient is recorded as having as many as
346 episodes. The incidence of this adverse event in the entire Integrated
Clinical Trials grouping is unknown (except for a single study, OMC-GHB-2)

·The few clinical descriptions of this adverse event
that are available in this NDA suggest that during “sleepwalking” episodes
patients may be confused and may act in a manner that could be prejudicial to
their own safety and that of others.

·The sponsor has not, so far, attempted to analyze this
adverse event as an entity

·The fairly high incidence and potential consequences of
such episodes make it essential that the sponsor should be asked to better characterize
the instances of sleepwalking in this NDA prior to the drug being approved for
marketing.

·In this reviewer’s opinion (and on a largely
speculative basis) it is possible that the term “sleepwalking” as used in this
entity could be describing one or more of the following entities